The causes and progression of several neurological diseases are influenced by factors that control the stability of neural function. Yet the mechanisms that dictate neural excitation and inhibition are poorly understood. Many studies indicate that homeostatic signaling mechanisms participate in the regulation of neural function - in paricular by modulating the strength of synaptic connections. This proposal aims to clarify the mechanisms of synaptic homeostatic signaling. Prior work defined a role for a presynaptic CaV2.1 calcium channel in synaptic homeostasis. New data show that the cytoplasmic signaling molecule, Ephexin, is also essential for synaptic homeostasis, and it may act via CaV2.1 regulation. In vertebrates, the Ephrin ligand and EphA receptor act upstream of Ephexin, and Rho-type GTPases act downstream of Ephexin to control growth cone dynamics. We hypothesize that all of these molecules are involved in a homeostatic signaling pathway in the presynaptic neuron. The proposed experiments for the K99 mentored phase will test this hypothesis. The results should define the role Ephexin signaling plays in the context of synaptic homeostasis. For the ROD independent phase, candidate molecules already known to regulate calcium channel function and Eph/Ephexin/GTPase signaling will be tested for roles in synaptic homeostasis. The long-term goal of this research is to define signaling mechisms with direct relevance to the cause and progression of neural disease. CANDIDATE: The K99 portion of this reserach will be conducted in the laboratory of Dr. Graeme W. Davis at UCSF. In this environment, I will continue to augment my training, both in the lab as well as in seminars, professional meetings, and one-on-one meetings with UCSF faculty. I am committed to attaining a faculty position at a major research institution. As an independent investigator, I would like to continue my research into the regulation of neural activity. PUBLIC HEALTH RELEVANCE: Many neurological diseases result from nervous system instability, but it is not understood exactly how neural stability is normally maintained. Data show that a molecule called Ephexin helps to direct neural stability. This proposal is designed to clarify exactly how Ephexin performs this function;the results may ultimately lead to a better understanding of the cause, progression, and treatment of neural diseases.